Transdermal Fentanyl

PEP Topic

Constipation

Description

Fentanyl is an opioid analgesic drug. The transdermal delivery system is intended to allow passive diffusion of the medication over a long period of time while maintaining a constant therapeutic dose. Transdermal fentanyl has been evaluated for management of chronic cancer-related pain. Transdermal fentanyl also has been examined in relation to opioids by other routes for its effect on opioid-related constipation.

Study Purpose:

To compare transdermal fentanyl and sustained-released morphine in palliative care patients with cancer by measuring efficacy, tolerance, and quality of life (QOL).

Intervention Characteristics/Basic Study Process:

Patients received one treatment for 15 days, then the other for 15 days to compare which provided the greatest efficacy and QOL, and the fewest side effects. The null hypothesis was 50% of patients would prefer fentanyl and 50% would prefer morphine.

Sample Characteristics:

The study reported on a sample of 202 adult palliative care patients with cancer; 110 completed the study.

Mean patient age was 61.5 years.

The sample was 55% male.

Patients had a life expectancy greater than a month and were receiving a strong, stable dose of opioids.

Setting:

38 different palliative care centers in the United Kingdom

Study Design:

This was a randomized, open, two-period, crossover study.

Measurement Instruments/Methods:

QOL was assessed with World Health Organization (WHO) performance status (measured prestudy, post-study, and daily during the study) and the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire, which measures side effects, convenience, and effects on activities of daily living (ADLs) or careers (measured after each arm of the study). These tools have been validated for patients with advanced cancer.

Constipation and diarrhea were assessed with the EORTC scale prestudy and on days 8, 16, 23, and 31.

Daily diaries were used to record estimated sleep length, night awakening, daytime drowsiness, and use of rescue medications.

Memorial Pain Assessment Card was used BID for assessment of pain and mood.

Skin assessment was performed when removing patches.

Results:

The top reason patients withdrew from the study was because of adverse events.

Fentanyl was associated with significantly less constipation than morphine (p < 0.001). This was confirmed through multiple assessment mechanisms.

The remaining results did not pertain to constipation.

Limitations:

Patients were allowed short-acting morphine for breakthrough pain, which could alter the results for fentanyl; however, the results were still significant.

Having a "washout" period is unethical.

Some patients may have dropped out because of morphine withdrawal.

The study was not blinded; therefore, bias may exist according to delivery mechanism preference.

Fentanyl and morphine doses varied among individuals and were titrated, as needed, throughout the study.

Study Purpose:

To investigate constipation and the use of laxatives in patients with chronic cancer pain treated with oral morphine and transdermal fentanyl.

Intervention Characteristics/Basic Study Process:

Patients were switched from long-acting morphine to fentanyl patches. Fentanyl doses were calculated with a conversion table based on a 100:1 dose ratio. If the calculated fentanyl dose was higher than 2.4 mg/day = 100 ug/hour (more than 270 mg/day slow-release morphine), more than one patch was used. Patients were treated with oral slow-release morphine for at least six days (morphine phase) until they reported stable pain intensity scores of 40 or less on a visual analog scale (0 = no pain, 100 = worst pain imaginable) for at least two days. Analgesic therapy then was switched from oral morphine to transdermal fentanyl (fentanyl phase). Fentanyl patches were changed regularly after three days. Fentanyl doses were increased when patients reported inadequate pain relief or had to take more than six rescue medications per day. The study was terminated after 30 days of transdermal therapy. Patients who completed the study until day 17 or longer were included in an intraindividual comparison of laxative intake using the Wilcoxon rank test.

Sample Characteristics:

The study reported on a sample of 46 patients (29 males and 17 females).

Median patient age was 57.5 years (range 31-83).

Median patient weight was 62.5 kg, and median height was 172 cm.

Sites of primary cancer included gastrointestinal, head and neck, genitourinary, respiratory, breast, and hematologic.

Setting:

Germany, June 1995 to January 1996

Unclear if inpatient or outpatient; the researcher was based at the University of Cologne.

Study Design:

This was an open, sequential, multi-center study.

Measurement Instruments/Methods:

Patient diary recording of intensity on a 0 to 10 visual analog scale three times daily, frequency of breakthrough pain and use of as-needed medications, use of laxatives, and self-assessment of frequency and consistency of defecation.

European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QOL-C30), with 30 items that assesses nine symptoms and six dimensions of quality of life.

Blood pressure, heart rate, respiratory rate, and skin reaction at the site of fentanyl application were documented by the treating physician on days 0, 6, 12, 18, 24, and 30.

Results:

Forty-six patients were treated with slow-release morphine (7 were excluded in the morphine phase because stable analgesia could not be achieved), and 39 were switched to transdermal fentanyl.

Twenty-three patients completed the study. Two patients died from basic disease, 12 were excluded for various reasons, and two did not have enough data available for evaluation.

The frequency of bowel movements did not change significantly, but the use of laxatives was reduced in 23 and increased in 2 of 28 patients on transdermal fentanyl.

Conclusions:

The use of laxatives was reduced significantly with transdermal fentanyl.

Limitations:

This was an open study, so prejudices from staff or patients may have biased the results.

The site of primary tumor was situated in the gastrointestinal tract for about 25% of the patients; in those patients, constipation easily may have been caused by tumor growth.

It may be questioned whether the conversion from morphine to fentanyl really was equianalgesic. Therefore, less constipation may have been the consequence of lower equianalgesic opioid dosage.

Results may have been influenced by the high number of patients who dropped out of the study.

Difference in the degree of constipation experienced by patients between the two analgesics regimens should be confirmed in a randomized, double-blind study that takes into account both constipation and use of laxatives.

Short-acting morphine was used for breakthrough pain in both arms of the study; as a result, the patients on fentanyl also had morphine on board.

The laxative used was not standardized; whether this influenced the results is unclear.

The study was supported by a research grant from a pharmaceutical company.

Literature Evaluated:

Of the 117 trials retrieved, 11 were considered potentially eligible. The analysis included five trials. Three trials included patients with cancer, and two included patients without cancer. The quality of the reports was evaluated using the Jadad scale.

Sample Characteristics:

The studies reported on a total sample of 1,309 patients across all trials.

The sample included 652 patients who were treated with transdermal fentanyl and 657 who were treated with slow-release oral morphine.

The sample included 373 patients who were treated for cancer pain.

In some trials, patients were in palliative care programs.

Results:

Compared to slow-release oral morphine, transdermal fentanyl was associated with less constipation, urinary retention, and laxative use, as well as higher patient preference.

Slow-release oral morphine was associated with less nausea, diarrhea, and sweating.

Authors observed no significant differences between the two drugs in regard to overall safety or gastrointestinal safety, somnolence, anorexia, vomiting, hypoventilation, insomnia, or uncontrolled pain that called for opiate rescue doses.

Findings were stable following analysis of cancer and noncancer subgroups.

Conclusions:

Side-effect profiles of transdermal fentanyl and oral slow-release morphine differ, but in this analysis authors observed no significant differences in overall side effects and patient preference regarding the two approaches. Transdermal fentanyl appears to be a valid alternative to oral opiates.

Limitations:

The analysis included a small number of studies.

Two trials included in this evaluation were of low quality.

Not all trials used the same methods of equianalgesia.

Nursing Implications:

Findings should be interpreted with caution, given the limitations of this meta-analysis. Additional research comparing transdermal and other medication delivery routes for pain control is warranted. Transdermal opiates may be particularly useful for patients using opiate switching. Addressing individual patients' needs and concerns may mean that side-effect profiles play an important role in the selection of a medication delivery route.